Overexpression of MERTK Receptor Tyrosine Kinase in Epithelial Cancer Cells Drives Efferocytosis in a Gain-of-Function Capacity
Overexpression of MERTK Receptor Tyrosine Kinase in Epithelial Cancer Cells Drives Efferocytosis in a Gain-of-Function Capacity
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DOI：
10.1074/jbc.m114.570838
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发表时间：
2014-09-12
影响因子：
4.8
通讯作者：
Birge, Raymond B.
中科院分区：
文献类型：
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作者：
Nguyen, Khanh-Quynh N.;Tsou, Wen-I;Birge, Raymond B.
MERTK 是 TAM（TYRO3、AXL 和 MERTK）受体酪氨酸激酶的成员，在细胞生物学中具有复杂多样的作用。一方面，MERTK 的敲除会导致年龄依赖性自身免疫，其特征是凋亡细胞清除失败，而另一方面，癌症中 MERTK 的过度表达会驱动经典的癌基因途径，导致细胞转化。为了更好地了解细胞转化和胞吞作用之间的相互作用，我们在人 MCF10A 细胞（一种缺乏内源性 MERTK 的非致瘤性乳腺上皮细胞系）中稳定表达 MERTK。虽然 MCF10A 中 MERTK 的稳定表达导致运动性增强和 AKT 介导的化学保护作用，但与亲本 MCF10A 细胞相比，MERTK-10A 细胞并未在软琼脂中形成稳定的集落，也没有增强增殖。伴随化疗耐药性，MERTK 还刺激胞吞作用以实现功能获得。然而，与 AXL 不同，MERTK 激活高度依赖于凋亡细胞，这表明 MERTK 可能优先与磷脂酰丝氨酸相互作用。与这一想法一致，乳腺癌细胞 MDA-MB 231 中 MERTK 的敲低减少了胞吞作用，而 MERTK 的瞬时或稳定表达刺激了所有测试细胞系中的凋亡细胞清除。此外，具有较高内源性 MERTK 的人乳腺癌细胞表现出较高水平的胞吞作用，这种作用可以被可溶性 TAM 受体阻断。最后，通过 MERTK，凋亡细胞诱导 PD-L1 表达（一种免疫检查点阻断），表明癌细胞可能采用 MERTK 驱动的胞吞作用作为免疫抑制机制，以发挥其优势。这些数据共同确定 MERTK 是癌症进展和胞吞作用之间的重要联系，并且当 MERTK 在上皮细胞中过度表达时，可能是未实现的肿瘤促进事件。
MERTK, a member of the TAM (TYRO3, AXL, and MERTK) receptor tyrosine kinases, has complex and diverse roles in cell biology. On the one hand, knock-out of MERTK results in age-dependent autoimmunity characterized by failure of apoptotic cell clearance, while on the other, MERTK overexpression in cancer drives classical oncogene pathways leading to cell transformation. To better understand the interplay between cell transformation and efferocytosis, we stably expressed MERTK in human MCF10A cells, a non-tumorigenic breast epithelial cell line devoid of endogenous MERTK. While stable expression of MERTK in MCF10A resulted in enhanced motility and AKT-mediated chemoprotection, MERTK-10A cells did not form stable colonies in soft agar, or enhance proliferation compared with parental MCF10A cells. Concomitant to chemoresistance, MERTK also stimulated efferocytosis in a gain-of-function capacity. However, unlike AXL, MERTK activation was highly dependent on apoptotic cells, suggesting MERTK may preferentially interface with phosphatidylserine. Consistent with this idea, knockdown of MERTK in breast cancer cells MDA-MB 231 reduced efferocytosis, while transient or stable expression of MERTK stimulated apoptotic cell clearance in all cell lines tested. Moreover, human breast cancer cells with higher endogenous MERTK showed higher levels of efferocytosis that could be blocked by soluble TAM receptors. Finally, through MERTK, apoptotic cells induced PD-L1 expression, an immune checkpoint blockade, suggesting that cancer cells may adopt MERTK-driven efferocytosis as an immune suppression mechanism for their advantage. These data collectively identify MERTK as a significant link between cancer progression and efferocytosis, and a potentially unrealized tumor-promoting event when MERTK is overexpressed in epithelial cells.